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Striking differences between knockout and wild-type mice in global gene expression variability.

ABSTRACT: Microarray analyses of gene knockouts have traditionally focused on the identification of genes whose mean expression is different in knockout and wild-type mice. However, recent work suggests that changes in the variability of gene expression can have important phenotypic consequences as well. Here, in an unbiased sample of publicly available microarray data on gene expression in various knockouts, highly significant differences from wild-type (either increases or decreases) are noted in the gene expression coefficients of variation (CVs) of virtually every knockout considered. Examination of the distribution of gene-by-gene CV differences indicates that these findings are not attributable to a few outlier genes, but rather to broadly increased or decreased CV in the various knockouts over all the (tens of thousands of) transcripts assayed. These global differences in variability may reflect either authentic biological effects of the knockouts or merely experimental inconsistencies. However, regardless of the underlying explanation, the variability differences are of importance as they will influence both the statistical detection of gene expression changes and, potentially, the knockout phenotype itself.

SUBMITTER: Eraly SA

PROVIDER: S-EPMC4022672 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Striking differences between knockout and wild-type mice in global gene expression variability.

Eraly Satish A SA

PloS one 20140515 5

Microarray analyses of gene knockouts have traditionally focused on the identification of genes whose mean expression is different in knockout and wild-type mice. However, recent work suggests that changes in the variability of gene expression can have important phenotypic consequences as well. Here, in an unbiased sample of publicly available microarray data on gene expression in various knockouts, highly significant differences from wild-type (either increases or decreases) are noted in the ge ...[more]

PMID: 24830645

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Project description:Microglia in the brain and macrophages in peripheral organs are cell types responsible for immune response to challenges. Indoleamine 2,3-dioxygenase 1 (IDO1) is an immunomodulatory enzyme of the tryptophan pathway that is expressed in the brain. The higher activity of IDO1 in response to immune challenge has been implicated in behavioral disorders. The impact of IDO1 depletion on the microglia transcriptome has not been studied. An investigation of the transcript networks in the brain microglia from IDO1-knockout (IDO1-KO) mice was undertaken, relative to peripheral macrophages and to wild-type (WT) mice under unchallenged conditions. Over 105 transcript isoforms were differentially expressed between WT and IDO1-KO within cell type. Within microglia, Saa3 and Irg1 were over-expressed in IDO1-KO relative to WT. Within macrophages, Csf3 and Sele were over-expressed in IDO1-KO relative to WT. Among the genes differentially expressed between strains, enriched biological processes included ion homeostasis and ensheathment of neurons within microglia, and cytokine and chemokine expression within macrophages. Over 11,110 transcript isoforms were differentially expressed between microglia and macrophages and of these, over 10,800 transcripts overlapped between strains. Enriched biological processes among the genes over- and under-expressed in microglia relative to macrophages included cell adhesion and apoptosis, respectively. Detected only in microglia or macrophages were 421 and 43 transcript isoforms, respectively. Alternative splicing between cell types based on differential transcript isoform abundance was detected in 210 genes including Phf11d, H2afy, and Abr. Across strains, networks depicted a predominance of genes under-expressed in microglia relative to macrophages that may be a precursor for the different response of both cell types to challenges. The detected transcriptome differences enhance the understanding of the role of IDO1 in the microglia transcriptome under unchallenged conditions.

Dataset Information

Striking differences between knockout and wild-type mice in global gene expression variability.

Publications

Striking differences between knockout and wild-type mice in global gene expression variability.

Similar Datasets

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